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Motexafin gadolinium (MGd) is a radiosensitizer that is MRI-detectable and selectively localizes in tumors.

MGd is an inhibitor of thioredoxin reductase, an enzyme whose overexpression is correlated with poor prognosis in NSCLC.

The 9801 trial randomized 401 patients with brain metastases from any solid malignancy and did not demonstrate a benefit with MGd.

A subgroup analysis of this randomized trial showed that there was a time-to-neurologic-progression (TNP) benefit from the addition of MGd to whole brain radiation (WBI) for metastatic NSCLC only (p=0.048).

That subgroup analysis prompted a randomized phase III trial of MGd in patients with intracranial NSCLC metastasis (the SMART trial).

In the SMART trial, the analysis of TNP by intent-to-treat, as measured from time from randomization, showed a benefit from MGd that did not reach statistical significance

It turned out that more patients in North America were promptly randomized after diagnosis of brain metastasis for planned WBI. However, in the other geographic sites, there was a delay attributed to the practice of treating brain metastases with chemotherapy before WBI (3% in North America vs. 32% in the rest of the world)

In the subset of North American patients (n=348), TNP was significantly increased by MGd: 8.8 months vs. 24.2 months, HR 0.53, p=0.004

In the subset of patients where WBI was initiated within 3 wks of diagnosis (n=378), TNP was significantly prolonged by MGd (HR 0.59, p=0.006).

Materials and Methods

This study was performed by pooling the data from the lung cancer patients in the 9801 trial with the data for patients treated on the SMART trial.

Patients were excluded for having liver metastases, extracranial metastases in 2 or more organs, prior whole brain radiotherapy or prior resection of a single brain metastasis.

The primary endpoint was time to neurologic progression or death with evidence of neurologic progression as determined by a blinded, centralized Events Review Committee (ERC).

The secondary endpoints included: time to neurologic progression as determined by the investigator, time to neurocognitive progression and survival.

In both trials, patients were randomized to receive either whole brain radiation therapy given to 30 Gy in 10 fractions or the same radiation given concurrently with motexafin 5 mg/kg/day x 10 days.

Results

The arms were well balanced in terms of patient related and disease specific prognosticators.

99% of patients received their intended complete course of WBRT, and 93% of intended motexafin doses were administered.

The median TNP as determined by the ERC was significantly improved in patients who received motexafin (15.4 months vs. 9.0 months, p=0.016).

The TNP as determined by investigator was significantly improved in the patients who received motexafin (HR 0.76, p=0.015).

The time to neurocognitive progression (as determined by 5 separate tests) was significantly improved in patients who received motexafin (HR 0.78, p=0.02)

The most common toxicity from motexafin is skin discoloration (74%); patients tend to turn green, although this usually disappears within 24 hours.

Author's Conclusions

Motexafin gadolinium significantly prolongs time to neurologic progression in NSCLC patients with brain metastases undergoing WBRT in a pooled analysis of two randomized trials.

Motexafin was well tolerated and did not compromise the delivery of WBRT.

Clinical/Scientific Implications

Unfortunately, the two initial studies of MGd combined with WBI were plagued by non-significant primary endpoint results, but had very intriguing subset analyses. There was a clear benefit to MGd in the subset of NSCLC patients in the 9801 trial and a benefit in North American and/or promptly treated patients in the SMART trial. By pooling data from these two trials, the investigators have been able to show that MGd appears to benefit patients. When it requires statistical maneuvers like this in order to demonstrate a benefit to a new drug, one needs to be somewhat skeptical regarding strong conclusions. However, this drug does appear to be safe to give and it does not interfere with radiation therapy delivery. Also, there really isn't much out there for patients with brain metastases from lung cancer. Further studies are indicated that are designed with clear statistical endpoints so that a strong conclusion on the efficacy of this drug can be made.